Significance Appropriate development of inflammation is essential to protect hosts from microbial infections, but inflammation can occasionally overshoot and cause collateral damage in hosts. Such hyperinflammation happens during endotoxemia and sepsis, and is attributed to excessive production of proinflammatory cytokines by host cells, such as macrophages. In this study, we demonstrate an unconventional mechanism by which T cells regulate cytokine production of macrophages. It is our general understanding that fast-acting immune cells (such as macrophages) “instruct” how T cells should behave through the step termed antigen presentation. However, what we show here is that T cells instruct macrophages to down-regulate a key proinflammatory cytokine, TNF, within hours after the initiation of endotoxemia.